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http://purl.uniprot.org/citations/19900447http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19900447http://www.w3.org/2000/01/rdf-schema#comment"

Background & aims

Induction of immediate early transcription factors (ITF) represents the first transcriptional program controlling mitogen-stimulated cell cycle progression in cancer. Here, we examined the transcriptional mechanisms regulating the ITF protein c-Myc and its role in pancreatic cancer growth in vitro and in vivo.

Methods

Expression of ITF proteins was examined by reverse-transcription polymerase chain reaction and immunoblotting, and its implications in cell cycle progression and growth was determined by flow cytometry and [(3)H]-thymidine incorporation. Intracellular Ca(2+) concentrations, calcineurin activity, and cellular nuclear factor of activated T cells (NFAT) distribution were analyzed. Transcription factor complex formations and promoter regulation were examined by immunoprecipitations, reporter gene assays, and chromatin immunoprecipitation. Using a combination of RNA interference knockdown technology and xenograft models, we analyzed the significance for pancreatic cancer tumor growth.

Results

Serum promotes pancreatic cancer growth through induction of the proproliferative NFAT/c-Myc axis. Mechanistically, serum increases intracellular Ca(2+) concentrations and activates the calcineurin/NFAT pathway to induce c-Myc transcription. NFAT binds to a serum responsive element within the proximal promoter, initiates p300-dependent histone acetylation, and creates a local chromatin structure permissive for the inducible recruitment of Ets-like gene (ELK)-1, a protein required for maximal activation of the c-Myc promoter. The functional significance of this novel pathway was emphasized by impaired c-Myc expression, G1 arrest, and reduced tumor growth upon NFAT depletion in vitro and in vivo.

Conclusions

Our study uncovers a novel mechanism regulating cell growth and identifies the NFAT/ELK complex as modulators of early stages of mitogen-stimulated proliferation in pancreatic cancer cells."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.org/dc/terms/identifier"doi:10.1053/j.gastro.2009.10.045"xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Singh G."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Buch T."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Schafer E."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Koenig A."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Gress T.M."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Hofmann L."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Adler G."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Fernandez-Zapico M.E."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Ellenrieder V."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Linhart T."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Kunsch S."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Reutlinger K."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Schlengemann K."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/author"Wegele J."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/pages"1189-99.e1-2"xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/title"NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells."xsd:string
http://purl.uniprot.org/citations/19900447http://purl.uniprot.org/core/volume"138"xsd:string
http://purl.uniprot.org/citations/19900447http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/19900447
http://purl.uniprot.org/citations/19900447http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/19900447
http://purl.uniprot.org/uniprot/#_A0A0B4J1R1-mappedCitation-19900447http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/19900447
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